Obstetrics and Gynecology

Pregestational DM

Pregestational diabetes during pregnancy

1. What every clinician should know

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by either absolute or relative insulin deficiency resulting in persistent hyperglycemia. Estimates of diabetes concurrent with pregnancy vary widely (from 5-14%), depending upon the population in question. Most with diabetes during pregnancy have gestational diabetes (GDM), a condition that arises for the first time during pregnancy and typically resolves after delivery. However, 10-15% have progestational DM—diabetes predating conception.

The pathophysiology of DM complicating pregnancy is heterogeneous. There are two major classifications for preexisting diabetes complicating pregnancy: type 1 diabetes formerly called insulin-dependent or juvenile onset diabetes and type 2 diabetes formerly referred to as noninsulin dependent disease or adult onset diabetes. The former is primarily an absolute insulin deficiency while the latter is characterized by a more prominent insulin resistant state. With the obesity epidemic combined with delayed childbearing in the United States, type 2 diabetes is by far more common than type 1 during pregnancy. Some common risk factors for type 2 diabetes during pregnancy include: increasing age, obesity, strong family history of type 2 diabetes, and nonwhite ethnic status—particularly Asian and Native American.

Pregestational DM is important to identify and manage prior to pregnancy, as significant hyperglycemia at the time of conception and the first trimester contributes to an increased risk of congenital birth defects and spontaneous abortion. Beyond the first trimester, DM contributes to an increased risk of stillbirth, abnormalities in fetal size (particularly macrosomia), shoulder dystocia and neonatal birth injury, neonatal metabolic abnormalities, and preeclampsia. Management can be challenging for both patient and provider, requiring frequent glucose monitoring, significant alterations in everyday diet, consistent insulin usage, and increased surveillance throughout pregnancy. These efforts improve glycemic control and reduce the risks of adverse perinatal outcomes.

2. Diagnosis and differential diagnosis

Many women are diagnosed with DM prior to becoming pregnant, often by internists or family medicine providers. This is accomplished by identifying a fasting glucose over 126 mg/dL, over 200 mg/dL (during a 2 hour 75 g oral glucose tolerance test-OGTT), or an hemoglobin A1c over 6.5%. Many DM women have not had medical care prior to pregnancy and remain undiagnosed until a routine GDM screening during pregnancy at 24 to 28 weeks gestation. Differentiating between newly diagnosed DM and GDM can be challenging, as there are no agreed upon methods to identify women with DM. These women carry the diagnosis of GDM until postpartum screening, when diabetes is found to be persistent. In general, a diagnosis of DM may be suspected during pregnancy with: an early GDM diagnosis if GDM is screened before 24 weeks, there is persistent diabetes after delivery, and/or an elevated baseline A1c (especially over 6.5%).

Maternal classification

The White classification is used to estimate the severity of DM during pregnancy (Table I). Important factors include: onset of disease, duration of disease, and degree of end-organ disease and vasculopathy. In the past when suboptimal glycemic control was the rule, this system was strongly predictive of adverse pregnancy outcomes as the duration of disease was closely related to end-organ damage and poor prognoses. Today, what is more relevant than duration of disease is the presence of underlying end-organ dysfunction and vasculopathy such as: chronic hypertension, nephropathy, retinopathy, and coronary artery disease.

Table I.

Class

Age

Duration

Vascular disease

A

Any

During pregnancy

No

A2

Any

During Pregnancy

No

B

>20 years

<10 years

No

C

10-19 years

10-19 years

No

D

Birth-10 years

>19 years

Benign retinopathy

F

Any

Any

Nephropathy

R

Any

Any

Proliferative retinopathy

H

Any

Any

Heart disease

T

Any

Any

History of transplant

3. Management

A. Baseline evaluation

An evaluation of maternal health at the first prenatal visit is required to understand the unique risks of each diabetic pregnancy. Given the common retinal and renal complications associated with longstanding DM, a retinal evaluation with an ophthalmologist, as well as an assessment of renal health, should be performed.

A baseline EKG may be performed for women with long-standing disease or hypertension. Thyroid dysfunction is commonly associated with DM and we have found an assessment for hypothyroidism useful. An hemoglobin A1c is useful for counseling concerning outcomes such as birth defects and spontaneous abortion, but the value beyond the initial evaluation may not be useful unless there is concern about the veracity of glucose data being given by the patient. A baseline maternal assessment is outlined in Table II.

Table II..

Organ system

Testing

Renal

Serum creatinine, 24-hour urine protein, and creatinine clearance

Vascular

Blood pressure, EKG (for long- standing disease)

Ophthalmology

Retinal evaluation

Infectious

Urine culture

Endocrine

Thyroid stimulating hormone

B. Antepartum management

B1. Glucose management. The management of diabetes revolves around strict glycemic control. Self–blood glucose monitoring along with intensive insulin therapy are standard care. Self-monitoring should be conducted before breakfast and 1 or 2 hours after breakfast, lunch, and dinner (postprandials) and occasionally at 2 to 4 a.m. to assess for nocturnal hypoglycemia. The use of postprandial levels, rather than preprandial levels, to guide therapy reduces the risk for macrosomia, neonatal hypoglycemia, and cesarean delivery for labor dystocia. Additional premeal values throughout the day may be added for more challenging patients.

Most women with pregestational diabetes are followed with outpatient visits at frequent intervals every 2 to 4 weeks. Email and fax communication allow for weekly communication of blood glucose levels and feedback regarding insulin dosing changes to be made without an outpatient office visit. Patients are instructed to call if either periods of recurrent hypoglycemia or sustained hyperglycemia (>200 mg/dL) without response to extra insulin dosing occur.

In women in whom diabetes is not well controlled despite outpatient efforts to improve glycemic status, hospitalization is advised. Hospitalization may also be necessary for women who do not have the skills to make necessary adjustments in early pregnancy to rapidly achieve euglycemia. Target blood glucose levels for pregnancy are found in Table III.

Table III.

Timing

mg/dL

Before breakfast

60-90

Before lunch, dinner, bedtime snack

60–105

Two hours after meals

120

2 a.m. to 6 a.m.

>60

B2. Nutrition management is essential for achieving euglycemia. Dietary composition should be 40% to 50% complex carbohydrates, 20% protein, and 30% to 40% fat, with less than 10% saturated fats. Caloric intake is based upon prepregnancy weight. Underweight women should expect to consume 30 to 35 kcal/kg/day while overweight women may require fewer. Women with a BMI greater than 30 may be managed with dietary intake as low as 15 kcal/kg/day of actual weight. Caloric distribution is recommended as follows: Breakfast 10% to 20%, lunch 20% to 30%, dinner 30% to 40%, and snacks up to 30% of total calories. If ketonuria develops, caloric intake may need to be increased.

B3. Medication

Semisynthetic insulins and newer insulin analogues are preferred for use during pregnancy. Insulin lispro or insulin aspart have replaced regular insulin as short-acting insulins, as they have a more rapid onset of action and shorter duration with less associated hypoglycemia. Long-acting insulin analogues (glargine and detemir) may more accurately mimic basal insulin compared to neutral protamine Hagedorn (NPH) insulin; however, the flat profile of glargine may be undesirable in pregnancy when variations in basal insulin needs are likely to occur. For this reason, it is often necessary to switch women receiving glargine to twice daily NPH insulin (morning and bedtime). A recent RCT comparing detemir to NPH insulin during pregnancy demonstrated comparable efficacy and detemir is now classified as a category B medication. Although NPH is an established staple, we commonly continue glargine or detemir for women who are taking these and are euglycemic at the onset of pregnency.

Insulin is administered in two to three injections. A three injection regimen is often used with the patient taking a combination of intermediate-acting (NPH) and short-acting insulin before breakfast followed by short-acting with dinner and bedtime NPH. Some women also require short-acting insulin to cover lunch, as well as snacks. The average daily insulin requirement for pregnant women with type 1 diabetes is 0.7 units/kg during the first trimester and increases to 1.1 units/kg by delivery. Intermediate insulin generally constitutes 50% to 66% of the total daily insulin dose, whereas short-acting insulin comprises approximately 33% to 50% of the daily requirement.

Because hypoglycemic episodes may result in significant untoward side effects, we use the weight based insulin requirements as a guideline rather than a rule. We follow glucose measurements for 1 week prior to initiation of insulin, identifying which portion of the day is associated with consistent hyperglycemic episodes. Insulins are begun at half the calculated weight-based dose and targeted to cover periods of hyperglycemia. Insulins are increased rapidly to obtain euglycemia.

Frequent evaluation of glucose values is essential once insulin is begun due to the progressive physiologic insulin resistance during pregnancy. Weekly increases in the insulin regimen is common. It is important to communicate to DM women that insulin requirements at the end of pregnancy are expected to be far higher than at the beginning.

Characteristics of insulins are noted in Table IV.

Table IV.

Type

Onset of Action

Peak Action

Duration of Action

Lispro

5-15 min

30-90 min

4-6 hr

Aspart

5-15 min

30-90 min

4-6 hr

Regular

30-60 min

2-3 hr

8-10 hr

NPH

2-4 hr

4-10 hr

12-18 hr

Glargine

2-4 hr

none

24 hr

Detemir

3-4 hr

none

20 hr

Randomized trials have not demonstrated a superiority of pump therapy when compared to multiple injection regimens. For women receiving continuous subcutaneous infusion (CSII) or “pump” therapy, rapid acting insulin is stored in the pump syringe. Infusion occurs at a basal rate, which is varied according to the time of day (frequently lower overnight) and preprandial boluses are given with meals and snacks.

Half of total daily insulin is usually given as the basal rate and the remainder as premeal boluses infused before each meal. Boluses are given as a carbohydrate ratio. For example, with a carbohydrate ratio of 1:8, one unit of insulin may be given for every 8 g of carbohydrates ingested.

Some women may also use a glucose sensor in addition to the pump. These sensors are equipped with alarms for impending high and low glucose values, and we have found they can be useful for reducing dangerous symptomatic low glucose values in women who have frequent and unpredictable hypoglycemic episodes.

Oral agents may be used for the management of type 2 diabetes, although the ADA recommends insulin as first line therapy during pregnancy. ACOG recommends individualization of therapy with the understanding that unlike insulin, oral agents do cross the placenta and long-term safety data are unavailable. In practice, women with type 2 diabetes who are well controlled on metformin are often continued on this therapy after appropriate counseling. This agent does not appear to be teratogenic. Long-term studies on exposed offspring are not yet available but are in progress.

B4. Antepartum Fetal Evaluation (Table V)

Table V.

Testing

Gestational age

Early dating ultrasound

As early as feasible

Detailed anatomic survey (Level 2)

18-20 weeks

Fetal echocardiogram

20-22 weeks

Antenatal surveillance (2x/week)

Starting at 32 weeks

Fetal growth scan

36-38 weeks, commonly offered on a monthly basis in the third trimester

Congenital birth defects are a common complication for women with suboptimal glucose management during the time of conception and the early first trimester. As such, we offer a detailed anatomic survey (18 to 20 weeks) and fetal echocardiogram (20 to 22 weeks) to identify concerns before delivery.

Maternal hyperglycemia may result in fetal hyperinsulinemia, which may increase the risk for fetal hypoxemia. For this reason, algorithms for care for diabetic pregnancy include a program of fetal surveillance during the third trimester. Improved maternal glycemia has reduced stillbirth risk in pregnancies complicated by diabetes such that antepartum fetal testing is employed primarily to reassure the obstetrician and avoid unnecessary premature delivery. Most tests of fetal well-being have few false-negatives. In practice, we have all pregestational diabetic women perform daily assessment of fetal activity during the third trimester. Non–stress testing (NST) is a primary method of fetal surveillance, which is followed by a biophysical profile (BPP) or contraction stress test (CST) if there is a concern. We prefer that NSTs be done twice weekly after the patient reaches 32 weeks. In women with vascular disease or suboptimal control, testing is often initiated earlier because of the increased fetal risk.

The results of fetal surveillance testing and clinical features should be factored in before intervening for suspected fetal compromise, especially in preterm gestation. In general, delivery should be delayed until fetal maturation has taken place, provided that diabetes is well controlled and antepartum fetal surveillance remains reassuring. In women who are well controlled without vasculopathy, delivery is not advised until 39 weeks gestation.

Before undertaking delivery prior to 39 weeks gestation, depending on individual clinical circumstances, an amniocentesis may be performed to assess fetal lung maturity. Tests of fetal lung maturity appear to have the same predictive value in diabetic pregnancies as in the normal population. In practice, however, amniocentesis for lung maturity has become less common in the management of diabetic pregnancy as those cases at significant maternal-fetal risk (e.g., women with vascular disease) are often delivered at 37 to 39 weeks without such testing.

Fetal growth assessment. Ultrasound, despite its inherent limitations for estimating fetal size, is employed during the third trimester to assess fetal growth. The detection of fetal macrosomia, an important measurable risk factor for shoulder dystocia, may aid in planning the timing and mode of delivery. In practice, an ultrasound assessment of fetal size is recommended within four weeks of delivery.

C. Intrapartum management/mode of delivery

Choosing the route of delivery for the diabetic woman is controversial. Cesarean delivery rates as high as 50% are common in series reported in the literature. Notwithstanding the accuracy limitations of ultrasound estimation of fetal size, cesarean delivery has been employed to reduce the risk of traumatic delivery (brachial plexus injury) associated with shoulder dystocia. The risk for shoulder dystocia with a fetal weight exceeding 4000 g in a diabetic pregnancy is approximately 10% to 25% and over 25% when greater than 4500 g. At present the ACOG recommends consideration of cesarean section at an estimated weight at or exceeding 4500 g. Our approach is to consider cesarean delivery with an estimated fetal weight (EFW) between 4000 to 4500 g after evaluating obstetric history and clinical pelvimetry. When a large fetus is suspected, operative vaginal delivery is best avoided, particularly with a prolonged second stage due to its association with shoulder dystocia.

Control of maternal glucose levels during labor and delivery is important to reduce the risk of neonatal hypoglycemia. Target glucose control at 100 mg/dL (between 70 to 140 mg/dL) is recommended to reduce this risk.

Insulin should be given intravenously as boluses or by continuous insulin drip once maternal glucose levels exceed 140 mg/dL or earlier. During active labor, women with type 1 diabetes require a basal infusion of insulin; as labor progresses, the insulin requirement may be little to none and glucose infusion can be necessary to maintain glucose levels in the 70 to 90 mg/dL range.

When cesarean delivery is to be performed, we prefer an early morning start so as to best regulate maternal glycemia after an overnight fast. NPH insulin in the evening is given at a full dose. If surgery must be delayed, we administer one third to one half of the intermediate acting dose of insulin in the morning. For women using a pump, we will maintain their basal rates and frequently assess glycemia while waiting to begin the cesarean delivery.

D. Postpartum management/contraception

Following delivery, insulin requirements are significantly lower than pregnancy needs. We relax the objective of tight control for 24 to 48 hours. Women who deliver vaginally are switched to one third to one half of their end pregnancy insulin dosing. If the data are available and the patient was well controlled at the beginning of pregnancy, the insulin regimen at that time may be restarted. Some women with type 2 diabetes will not require insulin postpartum. Frequent glucose determinations are used to guide therapy. All diabetic women are encouraged to breastfeed. The insulin dosing may be somewhat lower in lactating women. Metformin appears to be compatible with breastfeeding.

The serious side effects of the combined estrogen/progesterone pill, including thromboembolic disease and myocardial infarction, have been reported by some to be increased in diabetic women using them. We restrict the use of estrogen containing oral contraceptive pills to diabetic women without vascular disease or additional risk factors, such as strong family history of myocardial infarction, stroke, or in those who use tobacco. For long-term contraception, long-acting progestins and intrauterine devices seem to be safe and compatible with diabetes.

4. Complications

Diabetic pregnancy is a high risk state with a variety of fetal and maternal complications that are considered. Increased risks of preterm birth, fetal macrosomia, congenital birth defects and spontaneous abortion, as well as stillbirth are all important concerns (reviewed in Prognosis). Many of these can be reduced with close attention to reducing the frequency of hyperglycemia. DKA may occur more frequently during pregnancy and there should be attention to its development, particularly when offering corticosteroids for early delivery concern.

Diabetic ketoacidosis (DKA) can occur in newly diagnosed diabetics and pregnancy may reduce the threshold to DKA. DKA may develop in pregnant women with blood glucoses as low as 200 mg/dL. Malaise, headache, nausea, and vomiting are common complaints. A pregnant woman with persistent hyperglycemia and nausea and/or vomiting over 12 hours should be evaluated for potential DKA. Dehydration accompanies DKA and therapy hinges on both correction of fluid and metabolic abnormalities (see Table VI). Once DKA is stabilized, the patient should be transported to a tertiary care facility. Fluid resuscitation and insulin infusion should be maintained, even in the face of normoglycemia until serum bicarbonate levels return to normal, indicating that acidosis has cleared.

DKA does represent a risk for fetal compromise; however, fetal resuscitation often accompanies correction of maternal acidosis. Thus, every effort should be made to correct maternal metabolic status before intervening on behalf of a preterm fetus.

Maternal hypoglycemia. In general, management of diabetes during pregnancy significantly improves outcomes with few risks. However, hypoglycemic agents, especially insulin and glyburide, may produce hypoglycemia, which may precipitate seizures and loss of consciousness. Educating the patient and the family concerning symptoms of hypoglycemia may be helpful, as well as easy interventions, such as quick carbohydrate intake in most cases and use of intramuscular glucagon in severe cases.

5. Prognosis and outcome

A. Complications from the disease—pregnancy related

There is an increased risk of first trimester spontaneous abortion attributed to hyperglycemia in the first trimester. The risk rises progressively with increasing hemoglobin A1c levels, and this risk is mitigated by good periconceptional and first trimester glycemic control.

Congenital malformations are the most important cause of perinatal loss in pregnancies complicated by type 1 and 2 diabetes. There is a twofold to sixfold increase in major malformations in the offspring of these women. Most organ systems are affected and cardiac defects (transposition, double outlet right ventricle, ventricular septal defects, truncus arteriosus) as well as CNS malformations (anencephaly, holoprosencephaly) and neural tube defects (NTD) are the most commonly found.

Impaired glycemic control and associated derangements in maternal metabolism appear to be the primary teratogenic factors involved in the pathogenesis of these malformations. Control of maternal glucose levels with near normalization of hemoglobin A1C while attempting conception can reduce the risk for malformations to a level approaching the nondiabetic population (approximately 2%). An A1c over 10% confers a risk as high as 20% to 25%. Targeted ultrasound examination at 18 to 22 weeks gestation, as well as fetal echocardiography, are recommended for all pregestational diabetic pregnancies in order to detect possible defects.

Preterm birth (PTB) risk is elevated. Risks of preeclampsia, co-morbid medical disease, and poor glycemic control seem to all be contributors. The etiology of spontaneous PTB remains unclear. At this time, offering cervical length screening or other common interventions to reduce PTB is not routinely employed.

Stillbirth in the past was a significant concern before insulin was widely available. Prior to modern antenatal surveillance techniques, intentional preterm birth was commonly the strategy of choice, as most losses occur in the late third trimester, after 36 weeks. The etiology remains unclear. Some losses occur with maternal acidemia due to DKA, while others may be a combination of fetal hyperinsulinemia and chronic hypoxia associated with suboptimal glycemic control.

Macrosomia. The most common problem that diabetic women face is excessive fetal growth; and therapy for diabetes revolves around prevention. Various definitions of fetal macrosomia are used: birthweight >4000 g, birthweight >4500 g, or birthweight >90% for gestational age. Macrosomia rates are high in women with gestational and pregestational diabetes, approximately 20% to 50%, compared to 10% in nondiabetic pregnancies. Neonates of mothers with diabetes have increased fat proportions and proportionally larger shoulders and abdominal circumferences than nondiabetics. This disproportion predisposes to shoulder dystocia and birth trauma. Risk of shoulder dystocia is as high as 5% to 23.1% over 4000 to 4500g and from 20% to 50% if greater than 4500 g. Brachial plexus injury, both transient and permanent, may occur with shoulder dystocia.

The American College of Obstetricians and Gynecologists (ACOG) suggests that a discussion about the mode of delivery be initiated when the fetal weight is estimated to be greater than 4500 g; however, some will initiate a discussion depending upon the obstetrical history when the EFW is between 4000 g and 4500 g.

Neonatal metabolic alterations are frequently identified. Neonatal hypoglycemia (<35 to 40 mg/dL) occurs rapidly after delivery. Fetal hyperinsulinemia and maternal hyperglycemia at the time of delivery place the fetus at risk. It is often the consequence of hyperinsulinemia in utero and is thus more common in large for gestational age (LGA) infants. The frequency of this complication is approximately 25%. Euglycemia during labor minimizes this risk.

Polycythemia, hyperbilirubinemia, and subsequent jaundice are frequent neonatal issues, possibly due to chronic hypoxia in utero.

From the maternal perspective, obstetrical risks due to diabetes include preeclampsia and high rates of cesarean section. Preeclampsia is seen frequently during diabetic pregnancy, especially with baseline maternal nephropathy or chronic hypertension. In general, the incidence is approximately 15% to 20% and closer to 40% to 50% with nephropathy. In women with GDM, treatment seems to reduce the risk of preeclampsia during pregnancy.

B. Impact on long-term health.

For the most part, pregnancy does not accelerate end-organ disease commonly associated with diabetes with or without pregnancy.

Renal disease develops in 25% to 30% of women with preexisting diabetes with a peak incidence at 16 years after diagnosis of disease. Class F diabetes (nephropathy) complicates approximately 5% to 10% of type 1 diabetic pregnancies and is defined as either reduced creatinine clearance or proteinuria of at least 300 mg in 24 hours measured during the first 20 weeks gestation.

While excretion of protein normally increases in women with underlying nephropathy as pregnancy advances, there is no evidence that pregnancy permanently affects renal function and thereby accelerates the progression of diabetic nephropathy. Nonpregnant individuals with microalbuminuria or incipient nephropathy are prescribed ACE inhibitors, which are renoprotective. However, these medications are contraindicated during pregnancy, as they may induce oligohydramnios and may be teratogenic.

Proliferative retinopathy represents neovascularization or growth of new potentially fragile retinal capillaries. These vessels may cause vitreous hemorrhage and scarring with retinal detachment resulting in vision loss. Pregnancy may increase the prevalence of background retinopathy or nonproliferative changes, such as streak-blob hemorrhages or cotton wool exudates; however, these changes do not threaten vision loss. Women with diabetes planning pregnancy should receive a skilled retinal exam as proliferative retinopathy may be successfully treated prior to pregnancy with laser photocoagulation and an associated 90% success rate. Conversely, if untreated, proliferative retinopathy may progress in up to 90% of cases with pregnancy and may not be responsive to treatment. Women with proliferative retinopathy have been advised to avoid Valsalva to reduce the risk of retinal hemorrhage with delivery, however studies are lacking to address whether cesarean or operative vaginal delivery is preferred for these women.

Cardiac disease. Class H diabetes refers to women with associated ischemic cardiac disease. A high index of suspicion for ischemic heart disease should be maintained in women with long-standing diabetes because anginal symptoms may be minimal and infarction may present as congestive heart failure. In our practice, women with 10 years or greater duration of diabetes, vascular disease, or hypertension undergo baseline EKG testing in early pregnancy and maternal echocardiogram when clinically indicated.

6. What is the evidence for specific management and treatment recommendations